Our research program focuses on five subject areas: (1) the nature of protection against malaria that is conferred to individuals carrying red blood cell (RBC) polymorphisms including hemoglobin C, hemoglobin S, hemoglobin E, alpha-thalassemia and G6PD deficiency; (2) the nature of naturally-acquired immunity to malaria and how it is influenced by RBC polymorphisms; (3) the molecular mechanisms by which RBC polymorphisms reduce the expression of PfEMP1, the main virulence factor of Plasmodium falciparum, on the surface of parasitized RBCs; (4) the contributions of parasite genetic and host immune factors to the clearance of P. falciparum-infected RBCs in patients treated with the antimalarial drug artesunate; and (5) the nature of the selective invasion of reticulocytes by Plasmodium vivax. In each of these areas we seek research advances that can improve the knowledge of disease processes and antimalarial drug resistance mechanisms in patients with malaria and thereby support the development of new antimalarial therapeutics and vaccines that aim to prevent illness and death. The research activities in our program are multidisciplinary and include four field studies in malarious regions of Africa and Southeast Asia as well as programs of basic laboratory investigation at NIH-sponsored laboratories in Mali and Cambodia.